Conformational sampling of the botulinum neurotoxin serotype a light chain: implications for inhibitor binding
Conformational sampling of the botulinum neurotoxin serotype a light chain: implications for inhibitor binding
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DOI：
10.1016/j.bmc.2004.10.026
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发表时间：
2005-01-17
影响因子：
3.5
通讯作者：
Bavari, S
中科院分区：
文献类型：
--
作者：
Burnett, JC;Schmidt, JJ;Bavari, S
肉毒杆菌神经毒素(BoNTs)是已知的最有效的生物毒素，因此被列为A类生物制剂。目前，针对BoNTs的唯一治疗方法包括预防性抗毒素和长期支持性护理。因此，迫切需要治疗方法来对抗暴露后的这些酶。在之前的研究中，我们确定了一些具有BONT血清A型轻链(BONT/A LC)金属蛋白酶活性的小分子非肽性铅抑制剂，并确定了这些分子的一个共同的药效团。在本研究中，我们重点研究了BONT/A LC底物结合缝隙内及周围氨基酸残基的动态移动如何影响抑制剂结合模式。研究了两种BONT/A液晶(PDB RECODES=3BTA和1E1H)的X射线晶体结构。这些分析结果表明，所研究的BONT/A LC的核心结构特征，包括α-螺旋和β-折叠，在1 ns的动力学轨迹中相对保持不变。然而，在两个被检查的结构中，在与底物结合裂隙接壤的表面环中观察到了构象柔性。我们的分析表明，这些环可能具有降低底物结合裂隙的溶剂可及性的能力，同时为抑制剂创造新的残基接触。讨论了底物结合裂隙内残基的环运动和构象/位置分析，涉及到BONT/A LC抑制剂的结合和我们共同的抑制药效团。这些研究的结果可能有助于未来识别/开发更有效的小分子抑制剂，利用BONT/A LC中新的结合接触。爱思唯尔有限公司出版。
Botulinum neurotoxins (BoNTs) are the most potent of the known biological toxins, and consequently are listed as category A biowarfare agents. Currently, the only treatments against BoNTs include preventative antitoxins and long-term supportive care. Consequently, there is an urgent need for therapeutics to counter these enzymes-post exposure. In a previous study, we identified a number of small, nonpeptidic lead inhibitors of BoNT serotype A light chain (BoNT/A LC) metalloprotease activity, and we identified a common pharmacophore for these molecules. In this study, we have focused on how the dynamic movement of amino acid residues in and surrounding the substrate binding cleft of the BoNT/A LC might affect inhibitor binding modes. The X-ray crystal structures of two BoNT/A LCs (PDB refcodes = 3BTA and 1E1H) were examined. Results from these analyses indicate that the core structural features of the examined BoNT/A LCs, including alpha-helices and beta-sheets, remained relatively unchanged during 1 ns dynamics trajectories. However, conformational flexibility was observed in surface loops bordering the substrate binding clefts in both examined structures. Our analyses indicate that these loops may possess the ability to decrease the solvent accessibility of the substrate binding cleft, while at the same time creating new residue contacts for the inhibitors. Loop movements and conformational/positional analyses of residues within the substrate binding cleft are discussed with respect to BoNT/A LC inhibitor binding and our common pharmacophore for inhibition. The results from these studies may aid in the future identification/development of more potent small molecule inhibitors that take advantage of new binding contacts in the BoNT/A LC. Published by Elsevier Ltd.